Non-pathogenic Sindbis virus causes hemorrhagic fever in the absence of alpha/beta and gamma interferons

The role of interferon-gamma (IFN-gamma) in antiviral innate immune responses during acute alphavirus infection is not well defined. We examined the contribution of IFN-gamma to the protection of adult inice from Sindbis virus (SB)-induced disease by comparing subcutaneous infection of mice lacking receptors for either IFN alpha/beta (A 129), IFN gamma (G 129) or both (AG 129) to normal mice (WT 129). While neither G 129 nor WT129 mice exhibited clinical signs of disease, infection of A129 or AG129 mice was fatal with AG129 mice succumbing more rapidly. Furthermore, AG129 mice developed signs of viral hemorrhagic fever (VHF), including extensive hepatocellular damage, inflammatory infiltrates in multiple organs and vascular leakage, which were significantly delayed and/or partially ameliorated during fatal A] 29 infections. We conclude that: (i) IFN alpha/beta is the primary mediator of innate immunity to SB infection, however; (ii) IFN-gamma is directly antiviral in vivo, acting before the adaptive immune response appears and; (iii) development of VHF may involve viral suppression of both IFN alpha/beta and IFN-gamma responses. (c) 2007 Published by Elsevier Inc.